Extravascular lung water (EVLW) is a sensitive prognostic indicator of pulmonary edema. Thus, EVLW may be an advantageous method of fluid management. This study aims to evaluate the outcomes of using EVLW and pulmonary artery wedge pressure (PAWP) as strategies for fluid management in patients with acute respiratory distress syndrome (ARDS).
Twenty-nine patients were randomly divided into the EVLW and PAWP groups. The survival rate, ICU (Intensive Care Unit) length of stay, duration of mechanical ventilation, acute lung injury scores, and oxygenation index of the EVLW and PAWP groups were compared.
No significant difference in the survival rates at 28 and 60 days (d) after treatment was found between the two groups (p = 0.542). The duration of mechanical ventilation and ICU length of stay were significantly lower (p < 0.05) in the EVLW group than in the PAWP group. The 7 d cumulative fluid balance was -783 ± 391 ml in the EVLW group and -256 ± 514 ml in the PAWP group (p < 0.05). Compared with the PAWP group, the EVLW group showed improved oxygenation index (p = 0.006).
EVLW for fluid management improved clinical results in patients with ARDS better than PAWP.
Acute respiratory distress syndrome; Extravascular lung water; Fluid management; Pulmonary artery wedge pressure
Bacteria influence site-specific disease etiology and the host’s ability to metabolize xenobiotics, such as polycyclic aromatic hydrocarbons (PAHs). Lung cancer in Xuanwei, China has been attributed to PAH-rich household air pollution from burning coal. This study seeks to explore the role of lung microbiota in lung cancer among never smoking Xuanwei women and how coal burning may influence these associations. DNA from sputum and buccal samples of never smoking lung cancer cases (n = 8, in duplicate) and controls (n = 8, in duplicate) in two Xuanwei villages was extracted using a multi-step enzymatic and physical lysis, followed by a standardized clean-up. V1–V2 regions of 16S rRNA genes were PCR-amplified. Purified amplicons were sequenced by 454 FLX Titanium pyrosequencing and high-quality sequences were evaluated for diversity and taxonomic membership. Bacterial diversity among cases and controls was similar in buccal samples (P = 0.46), but significantly different in sputum samples (P = 0.038). In sputum, Granulicatella (6.1 vs. 2.0%; P = 0.0016), Abiotrophia (1.5 vs. 0.085%; P = 0.0036), and Streptococcus (40.1 vs. 19.8%; P = 0.0142) were enriched in cases compared with controls. Sputum samples had on average 488.25 species-level OTUs in the flora of cases who used smoky coal (PAHrich) compared with 352.5 OTUs among cases who used smokeless coal (PAH-poor; P = 0.047). These differences were explained by the Bacilli species (Streptococcus infantis and Streptococcus anginosus). Our small study suggests that never smoking lung cancer cases have differing sputum microbiota than controls.
lung microbiota; 16S; carcinogenesis; lung cancer; bacteria; respiratory; pulmonary
Exposure to benzene, a known leukemogen and probable lymphomagen, has been demonstrated to result in oxidative stress, which has previously been associated with altered telomere length (TL). TL specifically has been associated with several health outcomes in epidemiologic studies, including cancer risk, and has been demonstrated to be altered following exposure to a variety of chemical agents. To evaluate the association between benzene exposure and TL, we measured TL by monochrome multiplex quantitative PCR in 43 workers exposed to high levels of benzene and 43 age and sex-matched unexposed workers in Shanghai, China. Benzene exposure levels were monitored using organic vapor passive dosimetry badges before phlebotomy. The median benzene exposure level in exposed workers was 31 ppm. The mean TL in controls, workers exposed to levels of benzene below the median (≤31 ppm), and above the median (>31 ppm) was 1.26 ± 0.17, 1.25 ± 0.16, and 1.37 ± 0.23, respectively. Mean TL was significantly elevated in workers exposed to >31 ppm of benzene compared with controls (P = 0.03). Our findings provide evidence that high levels of occupational benzene exposure are associated with TL. Environ. Mol. Mutagen. 55:673–678, 2014.
benzene; telomere length; telomeres; occupational exposure
Transient cerebral ischemia leads to endoplasmic reticulum (ER) stress. However, the contributions of ER stress to cerebral ischemia are not clear. To address this issue, the ER stress activators tunicamycin (TM) and thapsigargin (TG) were administered to transient middle cerebral artery occluded (tMCAO) mice and oxygen-glucose deprivation-reperfusion (OGD-Rep.)-treated neurons. Both TM and TG showed significant protection against ischemia-induced brain injury, as revealed by reduced brain infarct volume and increased glucose uptake rate in ischemic tissue. In OGD-Rep.-treated neurons, 4-PBA, the ER stress releasing mechanism, counteracted the neuronal protection of TM and TG, which also supports a protective role of ER stress in transient brain ischemia. Knocking down the ER stress sensor Eif2s1, which is further activated by TM and TG, reduced the OGD-Rep.-induced neuronal cell death. In addition, both TM and TG prevented PARK2 loss, promoted its recruitment to mitochondria, and activated mitophagy during reperfusion after ischemia. The neuroprotection of TM and TG was reversed by autophagy inhibition (3-methyladenine and Atg7 knockdown) as well as Park2 silencing. The neuroprotection was also diminished in Park2+/− mice. Moreover, Eif2s1 and downstream Atf4 silencing reduced PARK2 expression, impaired mitophagy induction, and counteracted the neuroprotection. Taken together, the present investigation demonstrates that the ER stress induced by TM and TG protects against the transient ischemic brain injury. The PARK2-mediated mitophagy may be underlying the protection of ER stress. These findings may provide a new strategy to rescue ischemic brains by inducing mitophagy through ER stress activation.
cerebral ischemia; endoplasmic reticulum stress; mitophagy; neuroprotection; PARK2
AIM: To study the effects of QHF-cisplatin on H22 hepatocellular carcinoma (HCC) and their mechanisms of action.
METHODS: Sixty BALB/c mice were randomly divided into a model group (n = 48) and a normal control group (n = 12). An HCC xenograft tumor was created by injecting H22 cells directly into the liver parenchyma of the mice. The 48 BALB/c mice in the model group were randomly divided into four groups: QHF, DDP (cisplatin), QHF plus DDP, and model control. The inhibitory effects of these drugs on tumor growth were evaluated by calculating the rate of tumor growth inhibition. The mice were examined by observing their general condition, body weight and survival time. Changes in tumor tissue were observed under an optical microscope. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and α-fetoprotein (AFP) levels in serum were measured. Hepatocyte growth factor (HGF), c-mesenchymal-epithelial transition (c-Met) factor, phosphorylated (p)-c-Met, p38, p-p38, extracellular signal-regulated kinase (ERK), p-ERK and vascular endothelial growth factor (VEGF) levels were evaluated in tumor and liver tissues using western blotting.
RESULTS: Compared with the DDP group, a lower incidence of toxic reactions and a higher survival time were observed in the QHF plus DDP group. Tumor weight was significantly lower in the QHF, DDP and QHF plus DDP groups than in the model control group (0.24 ± 0.07, 0.18 ± 0.03 and 0.14 ± 0.01 g vs 0.38 ± 0.05 g, respectively), and the differences were statistically significant (P < 0.01). The rate of tumor growth inhibition in the QHF, DDP and QHF plus DDP groups was 38.7%, 52.6% and 63.5%, respectively. AST, ALT and AFP levels in serum were significantly lower in the QHF, DDP and QHF plus DDP groups compared to the model control group (P < 0.05). Similarly, HGF, p-c-Met, p-p38, p-ERK and VEGF levels in tumor tissue were significantly lower in the QHF, DDP and QHF plus DDP groups (P < 0.05).
CONCLUSION: QHF and DDP have an antiangiogenic effect on H22 HCC in mice. QHF inhibits tumor growth via blocking the HGF/c-Met signaling pathway, inhibiting p38, ERK and VEGF signaling.
QHF formula; Cisplatin; Hepatocellular carcinoma; H22 cells; Hepatocyte growth factor; c-Met
We isolated a novel monomeric peptide from antler plate polypeptide (APP) of sika deer and found that it inhibited rat breast cancer cell proliferation and telomerase activity.
The molecular mass and purity of this polypeptide was determined by ultra performance liquid chromatography (UPLC) and Bruker micOTOF OllQ TOF mass spectrometry, respectively. The full amino-acid sequence of the monomeric peptide was analyzed by sequential Edman degradation using a protein/peptide sequencer. The APP-1 markedly inhibited rat breast cancer cell proliferation as determined with an 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H- tetrazolium bromide (MTT) assay. Then, we used flow cytometry to detect the effects of the monomeric peptide on cell cycle. Relative quantitative fluorescence PCR was used to analyze the expression level telomerase reverse transcriptase (TERT).
The molecular mass and purity of this polypeptide was 10646 Da and 91.2 %. Amino acid sequence analyses indicated that the N-terminal amino-acid sequence of this monomeric peptide was: MTKLE DYLEG IVNIF HQYSV. The results showed that monomeric peptide halted most cancer cells stagnating in the G0/G1 phase. The percentage of cells in the G0/G1 is higher than control group after the monomeric peptide treatment. Relative quantitative fluorescence PCR results showed that TERT gene expression level obviously decreased after treatment with the monomeric peptide compared with control group.
Collectively, the results suggest that this novel and monomeric APP has antitumor activities and imply that it is likely an important component of antitumor activities in antler plate polypeptide.
Sika; Antler plate; Monomer polypeptide; Antitumor activities; Cell proliferation
Small RNA (sRNA) play pivotal roles in reproductive development, and their biogenesis and action mechanisms are well characterised in angiosperm plants; however, corresponding studies in conifers are very limited. To improve our understanding of the roles of sRNA pathways in the reproductive development of conifers, the genes associated with sRNA biogenesis and action pathways were identified and analysed, and sRNA sequencing and parallel analysis of RNA ends (PARE) were performed in male and female cones of the Chinese pine (Pinus tabuliformis).
Based on high-quality reference transcriptomic sequences, 21 high-confidence homologues involved in sRNA biogenesis and action in P. tabuliformis were identified, including two different DCL3 genes and one AGO4 gene. More than 75 % of genes involved in sRNA biogenesis and action have higher expression levels in female than in male cones. Twenty-six microRNA (miRNA) families and 74 targets, including 46 24-nt sRNAs with a 5’ A, which are specifically expressed in male cones or female cones and probably bind to AGO4, were identified.
The sRNA pathways have higher activity in female than in male cones, and the miRNA pathways are the main sRNA pathways in P. tabuliformis. The low level of 24-nt short-interfering RNAs in conifers is not caused by the absence of biogenesis-related genes or AGO-binding proteins, but most likely caused by the low accumulation of these key components. The identification of sRNAs and their targets, as well as genes associated with sRNA biogenesis and action, will provide a good starting point for investigations into the roles of sRNA pathways in cone development in conifers.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1885-6) contains supplementary material, which is available to authorized users.
Pinus tabuliformis Carr; miRNA; siRNA; Parallel analysis of RNA ends (PARE); Male cones; Female cones
pH-sensitive chemical exchange saturation transfer (CEST) MRI holds great promise for in vivo applications. However, CEST effect depends on not only exchange rate and hence pH, but also on the contrast agent concentration, which must be determined independently for pH quantification. Ratiometric CEST MRI normalizes the concentration effect by comparing CEST measurements of multiple labile protons to simplify pH determination. Iopamidol, a commonly used X-Ray contrast agent, has been explored as a ratiometric CEST agent for imaging pH. However, iopamidol CEST properties have not been solved, determination of which is important for optimization and quantification of iopamidol pH imaging. Our study numerically solved iopamidol multi-site pH-dependent chemical exchange properties. We found that iopamidol CEST MRI is suitable for measuring pH between 6 and 7.5 despite that T1 and T2 measurements varied substantially with pH and concentration. The pH MRI precision decreased with pH and concentration. The standard deviation of pH determined from MRI was 0.2 and 0.4 pH unit for 40 and 20 mM iopamidol solution of pH 6, and it improved to be less than 0.1 unit for pH above 7. Moreover, we determined base-catalyzed chemical exchange for 2-hydrooxypropanamido (ksw=1.2*10pH−4.1) and amide (ksw=1.2*10pH−4.6) protons that are statistically different from each other (P<0.01, ANCOVA), understanding of which should help guide in vivo translation of iopamidol pH imaging.
chemical exchange saturation transfer (CEST); iopamidol; MRI; pH
Fibroblast activation and proliferation are important for fibroblast–myofibroblast transdifferentiation, a crucial process in the pathological changes that define renal interstitial fibrosis. The left–right determination factor (Lefty) is an important cytokine of the transforming growth factor (TGF)-β family, with two variants, Lefty-1 and Lefty-2, in mice. Lefty has diverse functions, such as the regulation of embryonic development, the inhibition of TGF-β1 signaling, and the suppression of tumor activity. However, whether Lefty-1 influences fibroblast activation and proliferation, and consequently prevents fibroblast–myofibroblast transdifferentiation, remains unclear. This study aimed to investigate whether Lefty-1 can attenuate TGF-β1-induced fibroblast–myofibroblast transdifferentiation in normal rat kidney interstitial fibroblast cells (NRK-49F), as well as the mechanisms underlying any effects. Results showed that the typical fibroblast cell morphology of NRK-49F cells was altered after TGF-β1 treatment and that Lefty-1 significantly prevented this change in a dose-dependent manner. Further analyses demonstrated decreased proliferating cell nuclear antigen, cyclin D1, collagen I(A1), alpha-smooth muscle actin, and fibronectin expression. Lefty-1 further induced remarkable reductions in TGF-β1-induced Smad3 and mitogen-activated protein kinase-10/c-Jun N-terminal kinase (JNK-3) signaling, and enhanced expression of the antifibrotic factor bone morphogenetic protein (BMP)-5. However, without TGF-β1, Lefty-1 had no effect on Smad3, JNK-3, and BMP-5 activation and fibroblast–myofibroblast transdifferentiation. Taken together, these findings indicate that Lefty-1 can alleviate TGF-β1-mediated activation and the proliferation of fibroblasts. Furthermore, Lefty-1 may prevent fibroblast–myofibroblast transdifferentiation in part via modulations of Smad3, JNK-3, and BMP-5 activities in the TGF-β/BMP signaling pathway.
Lefty-1; NRK-49F; fibroblast; myofibroblast; transdifferentiation
Streptomyces phage φC31 integrase induces efficient site-specific recombination capable of integrating exogenous genes at pseudo attP sites in human, mouse, rat, rabbit, sheep, Drosophila, and bovine genomes. However, the φC31-mediated recombination between attB and the corresponding pseudo attP sites has not been investigated in Capra hircus. Here, we identified eight pseudo attP sites located in the intron or intergenic regions of the C. hircus genome, and demonstrated different levels of foreign gene expression after φC31 integrase-mediated integration. These pseudo attP sites share similar sequences with each other and with pseudo attP sites in other mammalian genomes, and these are associated with a neighboring consensus motif found in other genomes. The application of the φC31 integrase system in C. hircus provides a new option for genetic engineering of this economically important goat species.
Bisphosphonates have been shown to inhibit and deplete macrophages. The effects of bisphosphonates on other cell types in the tumor microenvironment have been insufficiently studied. Here, we sought to determine the effects of bisphosphonates on ovarian cancer angiogenesis and growth via their effect on the microenvironment, including macrophage, endothelial and tumor cell populations.
Using in vitro and in vivo models, we examined the effects of clodronate on angiogenesis and macrophage density, and the overall effect of clodronate on tumor size and metastasis.
Clodronate inhibited the secretion of pro-angiogenic cytokines by endothelial cells and macrophages, and decreased endothelial migration and capillary tube formation. In treated mice, clodronate significantly decreased tumor size, number of tumor nodules, number of tumor-associated macrophages and tumor capillary density.
Clodronate is a potent inhibitor of tumor angiogenesis. These results highlight clodronate as a potential therapeutic for cancer.
anti-angiogenesis; bisphosphonate; clodronate; ovarian cancer; tumor angiogenesis; tumor microenvironment; tumor-associated macrophages
We investigated the relationship between telomere length and lung cancer in a pooled analysis from three prospective cohort studies: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, conducted among men and women in the United States, and previously published data from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) trial conducted among male smokers in Finland, and the Shanghai Women's Health Study (SWHS), which is comprised primarily of never-smokers. The pooled population included 847 cases and 847 controls matched by study, age, and sex. Leukocyte telomere length was measured by a monochrome multiplex quantitative PCR assay. We used conditional logistic regression models to calculate odds ratios (OR) and their 95% confidence intervals (CI) for the association between telomere length and lung cancer risk, adjusted for age and pack-years of smoking. Longer telomere length was associated with increased lung cancer risk in the pooled analysis (OR(95% CI) by quartile: 1.00; 1.24(0.90–1.71); 1.27(0.91–1.78); and 1.86(1.33–2.62); P-trend=0.000022). Findings were consistent across the three cohorts and strongest for subjects with very long telomere length, i.e., lung cancer risks for telomere length (OR(95% CI)) in the upper half of the fourth quartile were 2.41(1.28–4.52), 2.16(1.11–4.23) and 3.02(1.39–6.58) for the PLCO trial, the ATBC trial, and the SWHS, respectively. In addition, the association persisted among cases diagnosed more than six years after blood collection and was particularly evident for female adenocarcinoma cases. Telomere length in white blood cell DNA may be a biomarker of future increased risk of lung cancer in diverse populations.
Leukocytes; Lung cancer; Prospective; Telomeres
Aquaporins (AQPs) function to selectively control the flow of water and other small molecules through biological membranes, playing crucial roles in various biological processes. However, little information is available on the AQP gene family in bananas. In this study, we identified 47 banana AQP genes based on the banana genome sequence. Evolutionary analysis of AQPs from banana, Arabidopsis, poplar, and rice indicated that banana AQPs (MaAQPs) were clustered into four subfamilies. Conserved motif analysis showed that all banana AQPs contained the typical AQP-like or major intrinsic protein (MIP) domain. Gene structure analysis suggested the majority of MaAQPs had two to four introns with a highly specific number and length for each subfamily. Expression analysis of MaAQP genes during fruit development and postharvest ripening showed that some MaAQP genes exhibited high expression levels during these stages, indicating the involvement of MaAQP genes in banana fruit development and ripening. Additionally, some MaAQP genes showed strong induction after stress treatment and therefore, may represent potential candidates for improving banana resistance to abiotic stress. Taken together, this study identified some excellent tissue-specific, fruit development- and ripening-dependent, and abiotic stress-responsive candidate MaAQP genes, which could lay a solid foundation for genetic improvement of banana cultivars.
Aquaporin (AQP); abiotic stress; banana; development; expression analysis; fruit postharvest ripening
Thin-film field-effect transistor is a fundamental component behind various mordern electronics. The development of stretchable electronics poses fundamental challenges in developing new electronic materials for stretchable thin-film transistors that are mechanically compliant and solution processable. Here we report the fabrication of transparent thin-film transistors that behave like an elastomer film. The entire fabrication is carried out by solution-based techniques, and the resulting devices exhibit a mobility of ∼30 cm2 V−1 s−1, on/off ratio of 103–104, switching current >100 μA, transconductance >50 μS and relative low operating voltages. The devices can be stretched by up to 50% strain and subjected to 500 cycles of repeated stretching to 20% strain without significant loss in electrical property. The thin-film transistors are also used to drive organic light-emitting diodes. The approach and results represent an important progress toward the development of stretchable active-matrix displays.
Stretchable displays need stretchable electronics to control them. Here, the authors create transparent and deformable thin-film transistors comprised of silver nanowire-based electrodes, a carbon nanotube network channel and a polyurethane-co-polyethylene oxide dielectric made using solution-based techniques.
Subcortical ischemic vascular dementia (SIVD) caused by chronic cerebral hypoperfusion develops with progressive white matter and cognitive impairments, yet no effective therapy is available. We investigated the temporal effects of minocycline on an experimental SIVD exerted by right unilateral common carotid arteries occlusion (rUCCAO). Minocycline treated at the early stage (day 0–3), but not the late stage after rUCCAO (day 4–32) alleviated the white matter and cognitive impairments, and promoted remyelination. The actions of minocycline may not involve the inhibition of microglia activation, based on the effects after the application of a microglial activation inhibitor, macrophage migration inhibitory factor, and co-treatment with lipopolysaccharides. Furthermore, minocycline treatment at the early stage promoted the proliferation of oligodendrocyte progenitor cells (OPCs) in subventricular zone, increased OPC number and alleviated apoptosis of mature oligodendrocytes in white matter. In vitro, minocycline promoted OPC proliferation and increased the percentage of OPCs in S and G2/M phases. We provided direct evidence that early treatment is critical for minocycline to alleviate white matter and cognitive impairments after chronic cerebral hypoperfusion, which may be due to its robust effects on OPC proliferation and mature oligodendrocyte loss. So, early therapeutic time window may be crucial for its application in SIVD.
The combustion of
biomass and coal is the dominant source of household
air pollution (HAP) in China, and contributes significantly to the
total burden of disease in the Chinese population. To characterize
HAP exposure related to solid fuel use and ventilation patterns, an
exposure assessment study of 163 nonsmoking female heads of households
enrolled from 30 villages was conducted in Xuanwei and Fuyuan, two
neighboring rural counties with high incidence of lung cancer due
to the burning of smoky coal (a bituminous coal, which in health evaluations
is usually compared to smokeless coal—an anthracite coal available
in some parts of the area). Personal and indoor 24-h PM2.5 samples were collected over two consecutive days in each household,
with approximately one-third of measurements retaken in a second season.
The overall geometric means (GM) of personal PM2.5 concentrations
in Xuanwei and Fuyuan were 166 [Geometric Standard Deviation (GSD):2.0]
and 146 (GSD:1.9) μg/m3, respectively, which were
similar to the indoor PM2.5 air concentrations [GM(GSD):162
(2.1) and 136 (2.0) μg/m3, respectively]. Personal
PM2.5 was moderately highly correlated with indoor PM2.5 (Spearman r = 0.70, p < 0.0001). Burning wood or plant materials (tobacco stems, corncobs
etc.) resulted in the highest personal PM2.5 concentrations
(GM:289 and 225 μg/m3, respectively), followed by
smoky coal, and smokeless coal (GM:148 and 115 μg/m3, respectively). PM2.5 levels of vented stoves were 34–80%
lower than unvented stoves and firepits across fuel types. Mixed effect
models indicated that fuel type, ventilation, number of windows, season,
and burning time per stove were the main factors related to personal
PM2.5 exposure. Lower PM2.5 among vented stoves
compared with unvented stoves and firepits is of interest as it parallels
the observation of reduced risks of malignant and nonmalignant lung
diseases in the region.
Deep brain stimulation (DBS) is considered a safe and well tolerated surgical procedure to alleviate Parkinson’s disease (PD) and other movement disorders symptoms along with some psychiatric conditions. Over the last few decades DBS has been shown to provide remarkable therapeutic effect on carefully selected patients. Although its precise mechanism of action is still unknown, DBS improves motor functions and therefore quality of life. To date, two main targets have emerged in PD patients: the globus pallidus pars interna and the subthalamic nucleus. Two other targets, the ventralis intermedius and zona incerta have also been selectively used, especially in tremor-dominant PD patients. The main indications for PD DBS have traditionally been motor fluctuations, debilitating medication induced dyskinesias, unpredictable “off time” state, and medication refractory tremor. Medication refractory tremor and intolerable dyskinesia are potential palliative indications. Besides aforementioned targets, the brainstem pedunculopontine nucleus (PPN) is under investigation for the treatment of ON-state freezing of gait and postural instability. In this article, we will review the most recent literature on DBS therapy for PD, including cutting-edge advances and data supporting the role of DBS in advanced neural-network modulation.
Movement disorders; Subthalamic nucleus; Globus pallidus; Neural network; Brain modulation; Closed-loop
Notch pathway plays an important role in the growth of high-grade serous ovarian (HGS-OvCa) and other cancers, but its clinical and biological mechanisms are not well understood. Here, we found that the Notch pathway alterations are prevalent and significantly related to poor clinical outcome in patients with ovarian cancer. Particularly, Notch3 alterations, including amplification and upregulation, were highly associated with poor patient survival. Targeting Notch3 inhibited OvCa growth and induced apoptosis. Importantly, we found that DNM-mediated endocytosis was required for selectively activating Jagged-1-mediated Notch3 signaling. Cleaved Notch3 expression was the critical determinant of response to Notch-targeted therapy. Collectively, these data identify previously unknown mechanisms underlying Notch3 signaling and identify new, biomarker-driven approaches for therapy.
Residual disease (RD) following primary cytoreduction is associated with adverse overall survival in patients with epithelial ovarian cancer. Accurate identification of patients at high risk of RD has been elusive, lacking external validity and prompting many to undergo unnecessary surgical exploration. Our goal was to identify and validate molecular markers associated with high rates of residual disease.
We interrogated two publicly available datasets from chemonaïve primary high-grade serous ovarian tumors for genes overexpressed in patients with RD and significant at a 10% false discovery rate (FDR) in both datasets. We selected genes with wide dynamic range for validation in an independent cohort using qRT-PCR to assay gene expression, followed by blinded prediction of a patient subset at high risk for RD. Predictive success was evaluated using a one-sided Fisher’s exact test.
Forty-seven probesets met the 10% FDR criterion in both datasets. These included FABP4 and ADH1B, which tracked tightly, showed dynamic ranges >16-fold, and had high expression levels associated with increased incidence of RD. In the validation cohort (n=189), FABP4 and ADH1B were again highly correlated. Using the top quartile of FABP4 PCR values as a pre-specified threshold, we found 30/35 cases of RD in the predicted high-risk group (positive predictive value 86%), and 54/104 among the remaining patients (P=0.0002; odds ratio 5.5).
High FABP4 and ADH1B expression are associated with significantly higher risk of residual disease in high-grade serous ovarian cancer. Patients with high tumoral levels of these genes may be candidates for neoadjuvant chemotherapy.
Ovarian cancer; residual disease; neoadjuvant chemotherapy; biomarker; FABP4
Group A protein phosphatases 2Cs (PP2Cs) are essential components of abscisic acid (ABA) signaling in Arabidopsis; however, the function of group F2 subfamily PP2Cs is currently less known. In this study, TaPP2C1 which belongs to group F2 was isolated and characterized from wheat. Expression of the TaPP2C1-GFP fusion protein suggested its ubiquitous localization within a cell. TaPP2C1 expression was downregulated by abscisic acid (ABA) and NaCl treatments, but upregulated by H2O2 treatment. Overexpression of TaPP2C1 in tobacco resulted in reduced ABA sensitivity and increased salt resistance of transgenic seedlings. Additionally, physiological analyses showed that improved resistance to salt stress conferred by TaPP2C1 is due to the reduced reactive oxygen species (ROS) accumulation, the improved antioxidant system, and the increased transcription of genes in the ABA-independent pathway. Finally, transgenic tobacco showed increased resistance to oxidative stress by maintaining a more effective antioxidant system. Taken together, these results demonstrated that TaPP2C1 negatively regulates ABA signaling, but positively regulates salt resistance. TaPP2C1 confers salt resistance through activating the antioxidant system and ABA-independent gene transcription process.
Vandetanib is an oral tyrosine kinase inhibitor of VEGFR-2/3, EGFR and RET, which has demonstrated clinical activity as a single agent and in combination with taxanes. We explored the efficacy, safety and toxicity of docetaxel and vandetanib in women with recurrent ovarian cancer (OC).
Women with refractory or progressive OC were randomized 1:1 to docetaxel (75 mg/m2, IV)+vandetanib (100 mg daily, PO, D+V) or docetaxel (75 mg/m2,D). Up to 3 additional cytotoxic regimens for recurrence and prior anti-angiogenic agents (as primary therapy) were allowed. The primary endpoint was progression free survival (PFS). The study had 84% power to detect a PFS hazard ratio of 0.65, using a one-sided P of 0.1. This corresponds to an increase in median PFS from 3.6 months to 5.6 months. Patients progressing on D were allowed to receive single agent vandetanib (D→V).
131 patients were enrolled; 2 were excluded. 16% had received prior anti-angiogenic therapy. The median PFS estimates were 3.0 mos (D+V) vs. 3.5 (D); HR:0.99 (80% CI:0.79-1.26). 61 patients on D+V were assessable for toxicity; 20(33%) had treatment-related Grade (G) 4 events, primarily hematologic. Similarly, 17(27%) of 64 patients receiving D had G4 events, primarily hematologic. 27 evaluable patients crossed-over to V. 1/27(4%) experienced a G4 event. G3 diarrhea was observed in 4% D→V patients. Median OS was 14 mos (D+V) vs. 18 mos(D→V); HR(OS):1.25 (80% CI:0.93-1.68). Crossover vandetanib response was 4%(1/27 evaluable patients). High plasma IL-8 levels were associated with response to D+V.
Combination docetaxel+vandetanib did not prolong PFS relative to docetaxel alone in OC patients. No unexpected safety issues were identified.
Ovarian Cancer; Primary Peritoneal Cancer; Fallopian Tube Cancer; Epithelial Cancer; Chemotherapy; Taxanes; Vandetanib; Clinical Trial; Randomized phase II
Objective: To explore a simple and practical method for human primary lung cancer cells culture in vitro. Methods: Tumor specimens from 6 lung cancer patients were isolated with collagenase digestion cultured in vitro. Then the characteristics of these cells were analyzed and identified by optical microscope observation, hematoxylin-eosin staining, immunocytochemistry, immunohistochemistry and tumor nude mice inoculation experiments, respectively. Results: Except for the small cell lung cancer, the other 5 samples were successfully isolated and cultured. The cultured cells showed typical characteristics of malignant cells and positive for cytokeratin 7 and 19. Moreover, the cancer cells readily formed subcutaneous tumors in nude mice and the pathological images of the transplanted tumor were consistent with its tumor origin. Conclusion: The primary culture for human lung cancer cells can be successfully achieved with the method of collagenase digestion.
Lung cancer; primary cell culture; morphology; H-E staining; immunohistochemistry
Objectives: Association of MTA2 expression with presence, development, metastasis and prognosis of colorectal cancer (CRC) was investigated. Methods: 90 CRC-related cases with follow-up information were made into tissue microarrays according to the paired principle of cancer tissues and the adjacent tissues. Subsequently, the expression of MAT2 was detected with immunohistochemical analysis and SPSS software was finally utilized to analyze the relationships between experimental data and clinical indicatives. Results: Expression of MTA2 in CRC tissues were notably higher than their adjacent tissues (P < 0.001) and showed significant positive correlation with tumor grade (r2 > 0, P < 0.01). Moreover, survival analysis indicated that MTA2 expression in cancer tissues, serving as an independent correlation factor, was significantly correlated with poor prognosis (P = 0.004). Conclusions: MTA2 is a crucial biomarker that is closely related with prognosis of CRC and also a potential molecular target for evaluating the prognosis and treatment of CRC.
MAT2; CRC; tissue microarray; immunohistochemistry; biomarker; prognosis
Atherosclerotic lesions are accelerated in patients with diabetes. M1 (classically activated in contrast to M2 alternatively activated) macrophages play key roles in the progression of atherosclerosis. Since advanced glycation end products (AGEs) are major pathogenic factors and active inflammation inducers in diabetes mellitus, this study assessed the effects of AGEs on macrophage polarization. The present study showed that AGEs significantly promoted macrophages to express IL-6 and TNF-α. M1 macrophage markers such as iNOS and surface markers including CD11c and CD86 were significantly upregulated while M2 macrophage markers such as Arg1 and CD206 remained unchanged after AGEs stimulation. AGEs significantly increased RAGE expression in macrophages and activated NF-κB pathway, and the aforementioned effects were partly abolished by administration of anti-RAGE antibody or NF-κB inhibitor PDTC. In conclusion, our results suggest that AGEs enhance macrophage differentiation into proinflammatory M1 phenotype at least partly via RAGE/NF-κB pathway activation.
Ubiquitin-specific protease 22 (USP22) removes ubiquitin from histones, thus regulating gene transcription. The expression frequency and expression levels of USP22 were significantly higher in hepatocellular carcinoma (HCC) than in normal liver tissues. High USP22 expression in HCC was significantly correlated with clinical stage and tumor grade. Kaplan-Meier analysis showed that elevated USP22 expression predicted poorer overall survival and recurrence-free survival. High USP22 expression was also associated with shortened survival time in patients at advanced tumor stages and with high grade HCC. Multivariate analyses revealed that USP22 expression is an independent prognostic parameter in HCC. These findings provide evidence that high USP22 expression might be important in tumor progression and serves as an independent molecular marker for poor HCC prognosis. Thus, USP22 overexpression identifies patients at high risk and represents a novel therapeutic molecular target for this tumor.
hepatocellular carcinoma; ubiquitin-specific protease 22; prognosis; cancer biomarker